.\ I~­I

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Difference in Caspase-3 Expression among Benign,Borderline and Malignant Epithelial Type of

Ovarian TumorI Made Brammartha Kusuma', Ketut Suwiyoga', I Nyoman Gede Budiana\ I Wayan Juli Sumadi"

1.2,3 Department of Obstetrics and Gynaecology, Oncogynaecologi Division

"Department ofPatology Anatomi, Faculty of Medicine Udayana University / Sanglah Hospital Denpasar- Bali

Abstract: Background: Ovarian tumor is a worldwideproblem and mortality due to ovaria tumor is the highest among gynaecologicmalignant tumors. Epithelial type are the most common ovarian tumor. The distribution of benign ovarian epithelial tumors, borderlineand malignant causes a variety of tumor characteristics that lead to difficulties in its management. One of the genes that playa role inovarian tumors is caspase-3, which is a protease execution DNA fragmentation that malfunctioning, causing no apoptosis. Themalfunction results in slowed ovarian cell death process and uncontrolled proliferation of ovarian cells that cause carcinogenesis.Research purposes: To know the differences of caspase-S expression in benign, borderline and epithelial type malignant ovarian tumor.Research methods: A cross-sectional study was conducted fr9m?to. 'fin block samples of benign, borderline and malignant type ofep~thelial.ovariantumor. Caspase-J expression.w~s !!!f~.tf!Jd!I¥i1 . ""'no~410chemiC?1staining. Sta~isticalanaLy_siswas perf?rmedusing Chi-Square test Results: Wefound a sIKjffi.l;tl'fJt'tIifferencein spase-I ~p,res"slOnamong benign, borderline and maltgnantepithelial ovarian tumor (p=O.008),a signific(liwJdif/erencebetween benign and Jali}Jilhnt epithelial ovarian tumor (p = 0,004). We didnot flnd a significant differences of caspase-J Ixpression between benign and borderline (p = 0,304) as well as between malignant andborderline epithelial type ovarian tumors (p = 0,215). Conclusion: Caspase-S expression was higher in benign epithelial type ovariantumor and lower in borderline and malignant epithelial type of ovarian tumor.

1. Background

Keywords: caspase-3, immunohistochemistry, ovarian, epithe .

caspase that catalyzes the cleavage of specificcellular proteins. Caspase-3 activation is

Ovarian tumor grows rapidly and the mortality is still high. with DNA fragmentation and morphologicalUp to 90% cases is diagnosed at an advanced stage that is changes that lead to cell death (apoptosis). Caspase-3 worksdifficult to cured by surgerY.,,,,O.Echemotherapy. ]the ciently for cell.' . ion than other caspases.Highercommon type of ovarian tU11l0rsis epithelial type:!t9 of caspase-3 I to wider spectrum of divisioncases).' Epithelial ovarian "fu1drs can be classifi resWtsin apoptosisfbenign, borderline and maligqarlWAbout 80% of benign '""tumors occur in young woni'en".~es 20 to 45 years. Various immunohist~chemical studies were conducted toBorderline and malignant tumors ai,tmore common in older determine the rel;tiop.ship·between caspase-3 with thewomen (age 45 to 65 years)." Al1holJghthe incidence is occurrence of cancer in the last two decades. According tolower when compared to cervical and uterinetumors but Li et aI (2011), c.@Spase-3activation was detected in normalmalignant ovarian tumors ~ave th~ iiign~~l:!rp9rta.Ji~~",,tissqe'~rlt ~Quianot be identified in peritumoral or squamousAccordmgto Busmar (2010),m the Umted States t11¢r~~efe": ,cell tiss!lesin oral cancer."Lower expressionof caspase-3 in25.400 cases of ovarian malignant tumors with 14JOll' Jtumo~tissue compared with normal tissue indicate that thedeaths, which accounted for 56,3% of all female deaths due apoptotic process mediated by caspase-3 did not work andto malignant ovarian tumors in 2003. In 2008, the incidence eventually the cells developed into cancer. However,of ovarian tumors in the world reached 9,4 % with a different observation is found in breast cancer. Donovan etmortality rate 5,1%3 The number of ovarian malignant al (2003) reported that caspase-3 levels in breast cancertumors cases in Indonesia is 829, the third after cervical patients were significantly higher than in fibroadenoma as2.532 cases and 2.254 cases of breast." Karyana (2005) well as normal breast tissue.10 Caspase-3expression increasefound the incidence of malignant ovarian tumors at Sanglah the proliferation rate in malignant breast tissue. The role ofGeneral Hospital accounted for 35% of all gynecological caspase-3 in cancer development is still controversial. Tocancers, with a five-year survival rate only 15%.5 date, no research has been done on caspase-3 expression at

Sanglah Hospital. Taken into account the high incidence ofovarian tumors, we decided to examine the differences incaspase-3 expression among benign, borderline andmalignant epithelial type of ovarian tumors.

Invasion and metastasis of ovarian cancer are caused by anabnormal apoptosis regulation. Apoptosis is a programmedcell death with specific form and cellular changes. Thisprogramed death has two major pathways. i.e., intrinsic andextrinsic pathways. Both of these pathways result incytochrome-c release and caspase activation." Caspase is aclass of £Ysteinyl ~partate-~ecific 12roteasesthat is notactive (zymogens) in healthy cells. Caspase-3 is the most

2. Method

The study was conducted from July 2015 to December 2016in Obstetric and Gynecology Outpatient Clinic Sanglah

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_

M_' -s1~· ~=I~n~te~r~n~a~ti~.o_n~a~I~J~O~U~rn~a_l_o_f~S_C_ie~n_c~e_a~n~d~R~~~ea~r~C_h_(~IJ~S_R~)_lISSN (Online): 2319-7064Index Copernicus Value (2016): 79.571 Impact Factor (2017): 7.296

Hospital, Anatomy Pathology Laboratory Faculty ofMedicine, Udayana University / Sanglah Hospital andMedical Record Installation Sanglah Hospital, Denpasar.This is a cross sectional study using 40 samples of paraffinblocks.

Paraffin blocks of epithelial ovarian tumor was obtainedconsecutively from patients who had given a written consentand underwent laparotomy for tumor removal from July2015 to December 2016 at Sanglah Hospital. Paraffin blockswas prepared in Anatomy Pathology Laboratory, Faculty ofMedicine, Udayana University! Sanglah Hospital which isexamined to define a definite diagnosis of benign, borderlineand malignant epithelial ovarian tumors.

The inclusion criteria for this study were 1) paraffin blockswere examined histopathologically and concluded as benignepithelial type ovarian tumor, borderline and malignant; 2)Complete medical records include identity, age, parity,histopathologic diagnosis. While for the exclusion criteria ofthis study 1) Patients had undergone chemotherapy befor~surgery; 2) Damaged paraffin blocks. Caspase-3 expies,si?llwas examined in all three groCUps '~singimmunohistochemical techniques with lyovocastra 1MLyophilized Mouse Monoclononal Antibody CPP32(Caspase-3) stain from Leica Biosystem Newcastle Ltd­United Kingdom. The expression is measuredsemiquantitatively by counting the percentage of "'''''5''''cells recorded positive among the 200 malignant "l'lUl"llW

observed by Olympus light microscope (400xmagnification). Staining is considered positive when the cellnucleus and / or cytoplasm are brown. Scores were obtainedbased on the percentage of cell nuclei and ! or cytoplasm inposition (Table 1), with a score range of 0 when no cellnucleus and! or cytoplasm were unbounded, score +1 whenthe cell nucleus and / or cytoplasm were in less than 1%, thescore +2 when a cell nucleus and ! or cytoplasm that iscovered by 1-10% and score +3 when the cell nucleus and /or cytoplasm are over 10%. Caspase-3 expression iscategorized to be negative for a score of 0 and + 1, whilepositive caspase-3 expression for the score of +2 and +3(Figure 1)11

Tb11Th' f 3a e : e mterpretation 0 caspase- stammgPatterns of wear Score Category

No nucleus cell and / or cytoplasmcolored 0 NegativeThe nucleus cell and / or cytoplasmsmeared +1 Negative

less than 1%The nucleus cell and / or cytoplasmsmeared +2 Positive

1-10%';i.~ The nucleus cell and / or cytoplasmsmeared +3 Positive'''' " '. more than 10%

<.

Figure 1: Positive (left side) and negative (right side) expression of caspase-3

The data was analyzed using SPSS 6.0 for Windows. Onesample Kolmogorov-Smimov test for performed to test datanormality and Levene's test used for data homogenecity.Mean comparation of each variable was analyzed using OneWay Anova test. Chi-Square test used to evaluate thedifference in caspase-3 expression among all three groups oftumors.

3. Results

From 40 blocks of paraffin obtained, the proportion ofbenign epithelial ovarian tumor were 7 (17,5%), borderlineepithelial ovarian tumors 10 (25%) and malignant epithelialovarian tumors were 23 (57,5%). There were no significantdifference in mean values of age and parity across all threegroups (Table 2).

Table 2: Distribution of Age and Parity among All ThreeGroups

Malignant Borderline Benign

Variables Tumor Tumor Tumor(n=23) (n=10) (11=7) p

Average SD Average SD Average SDAge (vr) 44,57 11 04 48,40 11,94 34.29 19,16 0,090Parity 1,74 1,36 2,00 I 70 1,14 1,77 0,516

Chi square test was performed to determine the differencesin caspase-3 expression among all three groups. There was asignificant difference in caspase-3 expression betweenbenign, borderline and malignant epithelial type ovariantumors (p = 0,008) (Table 3).

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Table 3: Caspase-3 expression between benign, borderlined maliznant eni h li I .an ma ignant eprt e ra type ovanan tumor

Epithelial Ovarian Caspase-3x2 PTumor Negative Positive

Malignant 18 5Borderline 5 5 9,71 0,008Benign 1 6

There were no significant difference in caspase-J expressionbetween benign and borderline epithelial type ovariantumors (p> 0,05) (Table 4).

Table 4: Caspase-3 expression between benign andborderline epithelial type ovarian tumor

Epithelial Ovarian Caspase-3X2 PTumor Negative Positive

Borderline 5 5 2,30 0,304Benign 1 6

There was a significant difference of caspase-3 expressionbetween benign and malignant epithelial ovarian tumors (p =0,004) (Table 5).

Table 5: Caspase-3 expression betweeIll:l~hi8fi andmali ant epithelial e ovariantti'inor

P

9,46 0,004

There was no significant difference in caspase-3 expI~ssionbetween malignant and borderline epithelial type ovarian"tumors (p>0,05) (Table 6).

al (2012) obtained an average age of 38,1 years for benignovarian tumor and 38,2 years for malignant ovarian tumor. 14

The mean of parity in the benign type epithelial tumor groupin this study was 1.14 ± 1.77, borderline type was 2.0 ± 1.70and malignant was 1.74 ± 1.36. Jordan et al (2009) reportedthat history 2 or 3 births with a history of preterm labor wasassociated with 60% and 90% increased risk of ovariancancer, although the observation was not statisticallysignifi cant. 15

One sample (2.5%) was negative for caspase-3 expressionamong the benign group,S samples (12.5%) were negativeamong borderline, and 18 samples (45%) were negativeamong the malignant group. There was a significantdifference of caspase-3 expression between benign,borderline and malignant epithelial ovarian tumors. Budiana,et al (2013) found the same result that 44.4% of caspase-3positive expression and caspase-3 negative expression were55.6% in ovarian cancer. 16 Chen Wet al (2010) found 93.4%saspase-3 positive expression in benign ovarian tumors and\48:~% .m. ovarian cancer." This result showed the role ofcaspase-J' in th\i mechanism of apoptosis as an executioncaspase that' t11e higher caspase-3 expression means theapoptotic mechanism work properly. Similarly, if lowexpression of caspase-3 indicates a disturbance in theprocess of apoptosis which later became the cause of anadvanced stage of ovarian tumor. It can be explained thatcaspase-3 is highly expressed in a well function cell immunes)'~t~m, thus caspase-3 has an important role in theregulation of apoptosis in the immune system. 1,18

In benign epithelial ovarian tumors, we found 1 sample withnegative caspase-3 expression (14.3%) and 6 samples

?&~iwith positive e~l"ession. In borderline epithelial.. tumors we fo~g;:~ similar proportion of negative

positive caspase-3> expression, i.e, 5 samples (50%).There was no signifJc&lJ-t,)lifferencein caspase-3 expressionbetween benign and~borderline epithelial ovarian tumors(p=0,304). Unlike invasive ovarian carcinomas, borderlineovarian tumois "pave nuclear and cytoplasmic atypia(dis~m~uishing. part with benign tumors), absent / absent.stromal invasion (distinguishing part with malignant tumor),'upequal degree of epithelial cell proliferation withstratification cellular features include exceptional atypicalarchitecture and papillary projection formation. The absenceof a stromal invasion is a principle criteria rather than aborderline ovarian tumor. 19

MalignantBorderline 5

4. Discussion

Ovarian tumors can be classified as benign, bord7fIil'!.e a.I1dmalignant type. About 80% of benign tumors occur'it yotmg .'.women between the ages of 20 and 45 years. Borderline andmalignant tumors are more frequent among older agebetween 45 and 65 years. In this study, the mean age inbenign, borderline, and malignant group was 34,29 ± 19,16years; 48,40 ± 11,94 years; and 44,57 ± 11,04 years,respectively. This observation suggests that as the ageincreases, the incidence of ovarian tumors increases too. In2009, Ovarian Cancer National Aliance reported that theincidence of ovarian tumors will increase among womenolder than 45 years and decrease among women youngerthan 45 years." In 2012, IARC (International Agency forResearch on Cancer) reported that in Indonesia, ovariancancer was the second most prevalent gynecologic cancerafter cervical cancer with the incidence rate amounted to be9,664 cases in 2008. The age group between 41 to 50 yearsis the largest age group suffering from ovarian tumors asmany as 62.7 %. It was less prevalent among the age groupof31 to 40 years (10.8%)13 Another study by Choudhury et

Distinguishing borderline ovarian tumors with benignovarian tumors is important to avoid overdiagnosis.Hauptmann et al (2017) suggests that according to WHO2014 classification, most authors agree that more than 10%of histologically borderline cells are actually benign ovariantumors (e.g. cystadenoma or cystadenofibroma). On theother hand, serous cystadenoma with foci of cells withborderline epithelial characteristics and less than 10% of cellvolume is categorized as cystadenoma / fibroma with focalepithelial proliferation. From a multicenter cohort study, itwas reported that overdiagnosis of borderline ovarian tumorsoccurred in 11.5% (92/803) of patients.i" Kimio Ushijirna etal (2015) argues that frozen section results in mucinousborderline tumors often do not accurately reflect histologic

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cell structures.Different or discordant diagnosis occurred in34% of mucinous borderline tumors. Potential factors thataffect the accuracyof frozen diagnosis are tumor size greaterthan 10 em and borderline elements less than 10%. If thetumor weighs more than 1.360 grams, the discordant ratecan be SO%. In most cases (94%), there is a discordantdiagnosis in tumor with more than 13 em."

In this study, 8S.7% of epithelial ovarian tumors withpositive caspase-3 expression were benign and SO%wereborderline epithelial ovarian tumors, although theobservation were not significant. The magnitudeof caspase-3 positive expression in benign epithelial ovarian tumorssignifies that apoptosis still work well and good in positiveexpression of caspase-3 compared with no caspase-3expression of the cell. Cells with uncontrolled proliferationdue to gene abnormalities will avoid apoptosis. Withreduced caspase-3 expression, abnormal cells will continueto proliferate uncontrollably.It will present as cellular atypiaand the ongoing process of mitosis produces growth anddevelopmentof cells with poor differentiation.22

In this study, we found inverse pattern 'Q{ocaSpase-3expression between benign and malignant ~p1thelialovariantumors. Caspase-3 positive expression was observed in 6samples (IS%) of benign epithelial ovarian tumors and in Ssamples (12.S%) of malignant ovarian tumors. Meanwhile,caspase-3 negative expressionwas found in 1 sample (2,5~ "of benign epithelial ovarian tumor and in 18 samples (45of malignant ovarian tumor. There were sigI,rificdifference in the expression of caspase-3 between 'benignand malignanttypes of epithelial ovarian tumor (p=0.004).

In ovarian tumors, there is lack of caspase-3 transcripts andreduced expressionof caspase~3'protein.Positive ~~resslpis higher in the early stages QLbyarianepithelial!i~iJ~epithelial type (31%) cornparea/ag.vance stage "t16;~X,).

" { .The higher the level of caspase:'~;e"p.ression,the longer thesurvival of malignant ovarian '~u~or cells." Similarobservation were also reported bYi,Budiana,et al (2016).They reported that there was a negativerelationship betweencaspase-3 expression and the stage of dyari~ic~ger. Inearly-stage ovarian cancer, the rate of nega.tive!e~pn~ssionwas 4.8% while the negative expression for advarid'ld'stage"was 47.6%. Positive expression indicates that the apoptoticprocess still works properly and associated with early stagecancer. Contrary, a negative expression of caspase-3indicates an impaired apoptotic process. Impaired apoptoticregulation will result in uncontrolled proliferation.f Lowexpressionof caspase-3result in carcinogenesis.r'

Positive expressions were found in S (21.7%) out of 23malignant samples, and in 5 (50%) out of 10 borderlinesamples. Negative expression found in 78.3% (18 samples)of malignant samples and in 50% (5 samples) of borderlinesample. There was no significant difference of caspase-3expression between malignant and borderline epithelialovarian tumors (p=0,215). Similar observation was reportedby Cabral et al (2016) which found no difference in negativeexpressionofp53 between borderline (16.7%) and epithelialovarian malignant tumor (29.7%) (p=0.560). NegativeexpressionofpS3 increased epithelial type of benign ovariantumor, borderline to malignant. Protein-53 (p53) may stop

the progression of the cell cycle or activate apoptoticpathway if there has been an extension of DNA damage, Innormal cells, p53 is constantly degraded by MDM2 on thecell nucleus so that the cell cycle will stop and eventuallythe cell has a short half life time. When DNA damage hasoccurred, several factorswill causeMDM2phosphorylation.pS3 remains stable as well as cell levels will increase,providing transcription factors for some genes. TPS3mutation is common in overall human cancers includingepithelial ovarian type cancer, protein transcription becomesinactive resulting in immunity ! resistance to cell cycledegradation. Malignant ovarian tumors show the highestrates of expression when compared with borderline tumorsand benign ovarian tumors. This gradual increase in p53expression can be explained by the difference in life-ratesbetween wild-typeproteins (constantly degraded, short livedhalf-lives) and p53 mutations (immune I degradationresistant, long live half-lives). Although not statisticallysignificant, the increased percentage of pS3 negativeexpression in benign, borderline and malignant epithelialovarian tumors is consistentwith the theory.25

In(:reas'~drll'ega,!ve expression of caspase-3 sin malignantepithelial tumor type (78.3%) compared to borderline type(50%) indicates the formation of high amount of 3-caspaseantibodies in malignant tumors in order to induce cell deathor apoptosis. Similar observationwas reported by Carie et al(2013) who studied the immunoreactivity to specificantibodies in the ovaries. Antibodies against caspase-3 hasi?\1v' reactivity in serous borderline-type ovarian tumors andvery strong reactivity in malignant serous type ovarianumors, althoughthe associationwas not significant.26

5. Conclusions and Suggestions~l,:;,~';:'~~~_;

:_,t'

pression of cliSpase-3was demonstrated in benigne iiU ovarian tumor')urli lower expression in borderlinemalignant epi!he~i,filtype ovarian tumor. Further

research on caspase-lexpression is needed until caspase-3can be used lj.s'f!cne'w biomarker for early detection ofepithelialovarilm'.t\:imors.

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